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• TCELL PILOT ATAC-SEQ

  This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001001317

• Deep Sequencing of somatic cancer mutations

  We enriched a panel of cancer associated genes using the Custom Sure Select Target Enrichment Kit. Identified mutations were validated with deep sequencing in order to assess mutated allele frequencies more accurately.

  Dataset EGAD00001001313

• Chondromyxoid fibroma

  Chondromxoid fibroma is a benign tumour of bone with unknown underlying pathogenesis. To determine pathognomic genomic event in chondromyxoid fibroma whole genome sequencing will be undertaken to reconstruct rearrangements and find underlying mutations.

  Dataset EGAD00001001063

• Single-cell colony targeted DNAseq

  Targeted DNA sequencing was applied to colonies grown from single-cells of patient A.6. The protocol followed is described in https://doi.org/10.1038/s41467-021-21650-1 and the methods of the manuscript

  Dataset EGAD00001010193

• WGS of a pair of monozygotic twins with Castleman disease and an unaffected sibling.

  The affected twins have their lymph nodes and buccal swabs sequenced with WGS. The unaffected sibling have his/her buccal swab sequenced with WGS as control too.

  Dataset EGAD00001011118

• Ewings Sarcoma RNA-seq drug sensitivity

  Illumina RNA-Seq will be performed on four Ewing's sarcoma cell lines and two control cell lines. RNA was extracted from all the lines using a basic Trizol extraction protocol.

  Dataset EGAD00001000337

• CRU-Ukrainian National Research Center for Radiation Medicine Trio Study

  Data on transgenerational effects following nuclear accidents are important for understanding fully the consequences of parental exposure to ionizing radiation. Few studies to date have had adequate statistical power to detect effects of the magnitude expected based on animal data, and most have not been of low-dose, protracted exposures associated with nuclear accidents and their aftermath. Although, to date, scant use has been made of the new genomic technologies, in Chernobyl-exposed areas of Ukraine and Belarus, excess minisatellite mutations have been seen in children born after the accident. We propose a study of parent-child trios in which at least one parent was exposed to Chernobyl radiation as a clean-up worker (mean dose>=100 mGy) and/or evacuee from a contaminated area (mean >=50 mGy). The specific aims are to investigate the transgenerational and de novo mutation rates of the spectrum of genetic variants in trios, in particular looking at effects in children and mapping them to possible parental origin of the chromsoome. Together with long-term collaborators at the Research Center for Radiation Medicine (RCRM) in Kiev, epidemiologic data will be collected for up to 450 trios of parents with preconceptional doses and their unexposed offspring. We will use state-of-the-art genomic technologies to characterize the landscape of the genomes of the trios to determine whether parental radiation exposure is associated with genetic mutations transmitted to the offspring, by examining de novo mutation rates, minisatellite mutations, copy number alterations, and variations in telomere length. The analysis will be conducted in peripheral blood and/or buccal samples (when blood is not available) from complete father-mother-child trios. Doses to the gonads from the time of the accident to the time of conception will be reconstructed for all parents using existing records supplemented by interview data. Trio subjects will be selected from representative populations exposed to radiation from Chernobyl who are under active follow-up in the Clinico-Epidemiologic Registry at RCRM. To help identify specific effects of paternal and maternal radiation exposure, we will initially select sets of trio subjects in five categories: (1) exposed father, unexposed mother; (2) unexposed father, exposed mother; (3) both parents exposed; (4) both parents unexposed; and (5) a group of high dose "emergency workers" with acute radiation syndrome. All trio members will be invited to the RCRM outpatient clinic for collection of a 20 ml blood sample (or buccal cells for those who refuse phlebotomy). Both parents will be asked to complete a general questionnaire to obtain demographic and lifestyle data. Then one or both will complete detailed dosimetry questionnaires, based on forms used in previous collaborations with RCRM and administered by specially trained interviewers. Once 50 trios have been recruited (10 from each of the 5 exposure categories), we will conduct an interim evaluation of participation rates, sample collection and quality, and dose reconstruction in order to modify the protocol as needed. The analytical approach will be to correlate the extent, especially for de novo events of genetic alterations in the offspring with parental pre-conceptional radiation dose overall and by parental origin. The statistical power in relation to de novo mutations is very high, in excess of 90%, but somewhat lower for trends in minisatellite mutations. Study findings will contribute importantly to knowledge of the heritable effects of moderate- and low-dose radiation exposure in humans and to radiation risk projection. Eventually data from the Trio Study may be shared with the international community through dbGap.

  Study phs001163

• PAK4 inhibition improves PD-1 blockade immunotherapy

  Introduction with rationale and aims for study Immune checkpoint blockade therapies have significantly altered the current landscape of cancer treatment. However, this immunotherapy still fails more often than it succeeds. There are now evidences that the lack of tumour infiltration by immune cells is the main mechanism of primary resistance to PD‐1 blockade therapies for cancer. It has been postulated that cancer cell‐intrinsic mechanisms may actively exclude T cells from tumours, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. With the idea of finding potential drivers of immune exclusion, we performed RNA sequencing analysis of biopsies from melanoma patients and compared the transcriptomic differences of samples that where infiltrated with those that did not have immune infiltration. Methods RNAseq analysis of gene expressions on biopsies from melanoma patients treated with checkpoint blockade were analysed. We focused on the variable of "infiltration: yes or no,", e.g. tumors that were well infiltrated by immune cells with those that kept immune cells out. Sequencing revealed a list of genes whose expression differed between the infiltrated and noninfiltrated tumors. The kinase PAK4 stood out as a good candidate for inhibition treatment in the future as it was consistently enriched in the samples without immune infiltration. To test whether immunotherapy would work better if we deleted PAK4, we first knocked out PAK4, using CRISPR‐Cas9, in the ‐resistant melanoma cell line, B16. Then they injected the melanoma cells into mice and observed that PAK4 KO tumours now responded to PD‐1 blockade. In order to elucidate whether pharmacological inhibition of PAK4 could recapitulate the results observed in the B16 PAK4 KO tumours, we obtained the PAK4 inhibitor, KPT-9274, from Karyopharm Therapeutics. Indeed, inhibiting PAK4 in combination with anti‐PD‐1 immunotherapy significantly slowed the growth of the B16 melanomas more than either drug alone. Results and Conclusions Transcriptomic analysis of melanoma tumors that were well infiltrated by immune cells with those that kept immune cells out revealed a list of genes whose expression differed between the infiltrated and non-infiltrated tumours. The result suggests that p21 activated kinase 4 (PAK4) is enriched in non-responding tumour biopsies with low T cell and dendritic cell infiltration. In addition, PAK4 decreased WNT activity, a signalling pathway that has previously been involved in immune exclusion. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD‐1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of with the PAK4 inhibitor, KPT-9274, improved anti‐tumour responses compared to anti‐PD‐1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and lack of response to PD‐1 blockade, which could be reversed with PAK4 inhibition. The data establish a rationale for targeting this kinase with inhibitors in combination with immune checkpoint inhibitors for patients. Future work and data that we can anticipate for this study Oncogenic signalling pathways and specially the WNT signalling pathway, have been associated with lack of immune infiltration and resistance to PD‐1 blockade therapies. Here, we show that PAK4 overcome resistance to PD‐1 blockade while significantly decreases WNT signalling activity. Therefore, it constitutes the first potential druggable target that is able to reverse oncogenic driven immune cell exclusion. However, the fully mechanism whereby PAK4 sensitizes tumours to immunotherapy remains to be fully elucidated. It is necessary to address whether PAK4 inhibition overcomes resistance through WNT signalling inhibition or if other signalling pathways are involved in the observed phenotype.

  Study phs001919

• Acute Respiratory Distress Network Early Versus Delayed Enteral Feeding to Treat People with Acute Lung Injury or Acute Respiratory Distress Syndrome (ARDSNet EDEN-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-EDEN include bronchial lavage, plasma, DNA, and urine. Please note that use of biospecimens in genetic and non-genetic research is subject to a tiered consent. Objectives: To determine if initial lower-volume trophic enteral feeding would increase ventilator-free days (VFDs) and decrease gastrointestinal intolerances compared with initial full enteral feeding. Background: Mechanically ventilated patients cannot eat normally and if not fed for long periods become malnourished. Because malnutrition is associated with poor outcomes in critically ill patients, artificial nutrition is often provided, especially in those with acute lung injury (ALI) and with expected longer duration of mechanical ventilation. When feasible, enteral nutrition targeting full caloric needs has been advocated over parenteral nutrition. However, feeding intolerance and common care practices often serve as practical barriers to reaching recommended goals. Although confounded by indication and severity of illness, several observational studies have shown improved clinical outcomes, including fewer infections, shorter duration of mechanical ventilation, and lower mortality for patients receiving a higher percentage of calculated caloric needs. Nonetheless, the best timing, formulation, and amount of enteral nutrition remain unknown. Participants: A total of 1,000 participants were enrolled. Design: Participants were randomized, stratified by site and presence of shock at enrollment, to receive either trophic or full enteral feeding for the first 6 days of mechanical ventilation. The initial 272 patients were also simultaneously randomized to a separate trial (the OMEGA study) comparing a nutritional supplement containing omega-3 fatty acids and antioxidants with an isocaloric, isovolemic control in a 2 × 2 factorial design.The designated feeding strategy was initiated within 6 hours of randomization and continued until death, extubation, or day 6. The care of mechanically ventilated patients still receiving enteral feedings after day 6 was managed according to the full feeding strategy in both groups. In extubated patients who then required reintubation, enteral nutrition was restarted and managed according to the study protocol.In the full-feeding group, enteral nutrition was initiated at 25 mL/h and advanced to goal rates as quickly as possible. Gastric residual volumes were checked every 6 hours while enteral feeding was increased. Patients randomized to the initial trophic-feeding group had enteral nutrition initiated at 10 mL/h (10-20 kcal/h) for the first 272 patients who also received the omega-3 or control supplement (240 mL volume per day). After the data and safety monitoring board stopped the OMEGA portion of the factorial design, the initial trophic feeding rate was changed to 20 kcal/h to approximate the calories that had been delivered in the OMEGA study. Gastric Residual Volumes (GRVs) were checked every 12 hours during trophic feeding. In patients randomized to trophic feeding, enteral nutrition was advanced to full-energy feeding rates following the same protocol used for the full-feeding group if they were still receiving mechanical ventilation at 144 hours. Conclusions: There was no difference between groups with regard to the primary end point, VFDs to day 28. There also were no differences in 60-day mortality, organ failure−free days, ICU-free days, or the incidence of infection between groups. Similarly, there were no differences between groups in VFDs or survival when analyzed by body mass index category or when subsets of patients with shock or more severe lung injury (acute respiratory distress syndrome) were examined.JAMA. 2012 Feb 22;307(8):795-803

  Study phs004168

• Korea Epigenome Project(KEP), Korea National Research Institute of Health(KNIH)

  The KEP was launched in 2012 to produce 50 epigenomic sets on Korean chronic diseases related target cells with the participation on Internationsl Human Epigenome Consortium(IHEC) of which focus is constructing 1000 reference epigenome map on 250 human cell type. The objective of the KEP was to provide a comprehensive epigenomic map of Korean chronic disease-related target tissues. Single cells were isolated from the pancreas, fat and kidney. Islet, ductal, acinar, and beta cells from the pancreas were purified into a single homogenous cell type using flow-assisted cell sorting technique. Adipocytes and pre-adipocytes were purified from fat, using Percoll gradient centrifugation technique. Mesangial, distal tubule, proximal tubule, podocytes, and collecting duct cells from the kidney were collected using mechanical sieving and immunostaining methods. Each cell type was derived from normal tissue or those with diabetes, obesity, or chronic kidney disease. Sixty reference epigenome datasets of pancreatic, fat, kidney cells were produced. Cell types such as the islets, and beta from the pancreas, adipocytes, pre-adipocytes from fat tissue, podocyte, mesangial, tubules from kidney were used for primary target to produce a Korean metabolic reference epigenome. And the bisulfite converted-whole genome sequencing, Infinium 450k DNA methylation bead array, mRNA, miRNA-Sequencing were performed to produce a comprehensive epigenomic map. The aim of roadmap reports is preparation of Long-term and Mid-term Technology Roadmaps for Korean Human Epigenome Project towards a competitive execution of International Epigenome Project and successful expansion of the research outcomes. Roadmap reports reviewed on recent technological development of DNA methylation and histone modification analysis, emerging new trends in epigenome medicine, plans for hardware and software analysis systems aimed to epigenome analysis, medical expert opinion on target cells and isolation scheme, bioinformatics expert opinion on analytical tools, new ideas for a putative epigenome studies, trends in single cell epigenome analysis. In conclusion, roadmap report suggested several projects for the future KNIH epigenome research in collaboration with epigenome research group. These are including refocusing the goals of KNIH-driven research in identification of disease mechanism, development of new studies on GWAS-EWA, higher priority on the epigenomic studies of human primary cells, establishment of collaborative relationship with tissue banking centers, establishment of mapping centers and data analysis portals, establishment of Korean Epigenome Research Consortium, establishment of steering committee governing both research and funding, launching of additional funding for epigenomic researches.

  Study EGAS00001001774